Sulforaphane (Broccoli) for Cancer, Autism and COPD

A reference to the other Broccoli

One advantage this blog has is that it looks at the comorbidities of autism, so we are aware of useful findings in related areas.  So it then does not come as a big surprise when a therapy effective in related areas also helps with autism.

One of the most useful is asthma.  Chronic obstructive pulmonary disease (COPD) is a related condition, brought on by smoking or pollution.  It kills 3 million people a year; COPD is made much worse by chronic oxidative stress.  We saw in an earlier post that oxidative stress stops the asthma drugs from working.  The current treatment for oxidative stress in COPD is N-acetyl cysteine (NAC).  I recall they are still looking for a better treatment; perhaps the search is over.  (see later).

We also saw that there is already some overlap between “emerging” research findings in cancer and those in autism. These include:-

·        PAK1, mTOR (Rapamycin), Wnt signaling

·        Ivermectin treatment for Leukemia and Autism

·        Quercetin and NAC aiding recovery for specific cancers and helping some in autism

For twenty years researchers have known about the potential cancer fighting benefits of Sulforaphane, which is produced by a chemical reaction when you eat fresh broccoli that was only lightly cooked.

In the intervening years vast amounts of research has been going on to tinker with broccoli to maximize/harness the potential health benefit, and also to develop related synthetic drugs (analogs of Sulforaphane) like Sulforadex.

Twenty years later, and a vast amount of broccoli supplement pills later, not many people have benefitted.  When you look into the matter, it really is rather bizarre.

Fresh raw broccoli was found to contain large amounts of both Glucoraphanin and an enzyme called Myrosinase.  When you eat the raw broccoli the Glucoraphanin and Myrosinase react to produce a potent substance called Sulforaphane, which seems to have numerous positive effects.  A powerful anti-oxidative process is triggered that was shown to have a strong anti-cancer effect.

The problem is that myrosinase from broccoli is not stable; when you cook it, freeze it, or process it, you lose it.  So, soggy cooked broccoli, crisp frozen broccoli and almost all the broccoli pills on the market have no myrosinase and therefore no Sulforaphane will be produced.

There have been numerous studies showing this and also a few clever ideas to get around it have been investigated.

Sulforaphane is itself also unstable and has to be used immediately or kept frozen.

Johns Hopkins and Sulforaphane

Sulforaphane was discovered in 1992 at Johns Hopkins and much related research still comes from there.  They hold the key patents and indeed went as far as to try to stop other people growing/selling broccoli sprouts.  They have developed a way to produce Sulforaphane in the laboratory and then it is freeze dried and kept frozen at -20 Celsius.

Cancer research

The cancers where Sulforaphane has shown promise include:-

§  Carcinogen detoxification

• Tumor progression and activity
• Stomach cancer
• Skin tumors
• Breast cancer
• Prostate cancer
• Colon cancer
• Bladder cancer
• Impact on developing or developed cancers

COPD

What caught my attention was a paper from 2008 by Peter Barnes, one of only two Englishmen on my Dean’s list and the only one that lives there.

Defective Antioxidant Gene Regulation in COPD: A Case for Broccoli

This has been followed up and there is now a Phase 2 clinical trial of Sulforaphane for treatment of COPD.

Broccoli Sprout Extracts Trial (BEST)

Barnes is my kind of scientist.  He has noted that the most potent, safe antioxidant to treat COPD is NAC (N-acetyl cysteine) but he wanted more, and has been on the look-out for years for a stronger, but safe, alternative.  He concluded that

“It has been difficult to find new more effective antioxidants that are not toxic. A more attractive approach may be to restore Nrf2 levels to normal through inhibiting the action of Keap1. This has been achieved in vitro and in vivo by isothiocyanate compounds, such as Sulforaphane, which occur naturally in broccoli”

And finally to Autism

So the recent big news that Sulforaphane was remarkable successful in a small trial at Massachusetts General Hospital (MGH) and Johns Hopkins maybe should not be such a surprise.

Sulforaphane treatment of autism spectrum disorder (ASD)

Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medicoeconomic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled,double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 μmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

What surprised me was just how big an impact the Sulforaphane had and the fact that these are very serious researchers, unlike many others.

Since we are talking about a therapy that has a strong anti-oxidant connection I compared the trial results from the Stanford NAC trial, with those from the Sulforaphane trial at MGH.

Monty, aged 11 with ASD, responded almost immediately to NAC and so of course I am interested in any additional, even overlapping, therapy.

For anyone interested, the following table shows the results from the NAC study:-

The data shows a large drop in irritability and hyperactivity and a moderate improvement in stereotypy, compulsions and SIB.  On the Social Responsiveness Scale, the people on NAC dropped by 18 , versus a drop of 6 for the placebo group.

Now we have the results from the Sulforaphane (broccoli) study.

On the Social Responsiveness Scale (SRS) , the people on Sulforaphane dropped by 20, versus a drop of 2 for the placebo group.

Moving on to the Aberrant Behavior Checklist (ABC) we can compare the improvement in four sub-categories:-

NAC               Sulforaphane

Irritability                 -9.7                     -4

Lethargy                  -4.2                     -4.5

Stereotypy              -3.5                      -2.7

Hyperactivity           -11                      -4.8

Now these figures are averages.  In reality you are likely either a responder or non-responder, nobody is likely to be Mr. Average.

I found these results very encouraging, albeit less so than the NAC trial.  The Sulforaphane trial was conducted among young adults whereas NAC was trialed on children.  You might expect children to be more responsive, since their autism tends to be less controlled than it tends to be in adulthood.

Since both trials are drawn from a population with behavioral autism and not any biological specific dysfunction both groups will likely include people with :-

·        Classic early onset autism caused by multiple genetic and epigenetic (environmental) hits

·        Mitochondrial disease triggered regressive autism, with no inherent prior dysfunction

·        Single gene disorders, probably never identified

Any trial with responders > 30% is therefore very interesting.  This trial was much better than that.

Now, both classic autism and Mitochondrial disease triggered regressive autism are associated with oxidative stress.  People with classic autism do seem to respond to NAC, whereas some people with Mitochondrial disease do not.

In the NAC trial the dose was stepped up every 4 weeks  (0.9g 1.8g 2.7g).  In the Sulforaphane trial the dose remained the same but the effect grew.

So the method of action of both drugs may be similar, but it is not identical.  NAC is a ”primary anti-oxidant”, in that NAC and its end product Glutathione (GSH) are themselves anti-oxidants.   

Sulforaphane appears to be a “secondary anti-oxidant”, it activates Nrf2 which then triggers a set of reactions that promotes an anti-oxidant response.  So it is logical that there is a time delay.

But after week 18, Sulforaphane treatment was stopped and at week 22 all benefit had been lost.

So we can conclude, even though these are two different trials with different groups of people, that if anything NAC looks more potent than Sulforaphane.

The question is whether Sulforaphane plus NAC would be even better than NAC (or Sulforaphane) alone.

  

Mode of Action

I know that NAC is a “direct” anti-oxidant and it is a precursor for glutathione (GSH); its effect is almost immediate, whereas the MGH researchers inform us that Sulforaphane became effective over a matter of weeks.  We know that Sulforaphane activates a transcription factor, Nrf2 in the cell. Once activated, Nrf2 then translocates to the nucleus of the cell, where it aligns itself with the antioxidant response element (ARE) in the promoter region of target genes. The target genes are associated with process which assists in regulating cellular defences. Such cytoprotective genes include that for glutathione (GSH).

So it is clear that both NAC and Sulforaphane will affect the level of the boy’s most important antioxidant glutathione (GSH).

That may possibly be the end of the story.

Science does tell us that Sulforaphane has many other effects that may also be beneficial in autism.  They do seem to have an effect in cancer and some do relate to reversing epigenetic “errors”.  Classic autism is also likely triggered, in part, by epigenetic “markers” on undamaged parts of the DNA.  Any method of selectively removing these markers and turning genes “off” that were “on” in error and vice versa is very interesting.

Sulforaphane’s effect in cancer appears to be more than just an antioxidant.  Research has shown that it is indeed active epigenetically (switching on and off genes).

The logical next step would be to test NAC vs Sulforaphane vs (NAC + Sulforaphane).

Since we live in an imperfect world, rather than wait half a century for a clinical trial, you might have to do a home trial.

In the next post we will see how to make Sulforaphane at home.

As is often the case, it is not as simple as buying some on Amazon.

Sulforaphane survives for 30  minutes outside the freezer and almost all broccoli supplements have been shown to have no active Myrosinase.  Without this enzyme almost no Sulforaphane will be produced, no matter how many broccoli tablets you take.

This reminds me of people buying oxytocin over the internet.  If it is not kept chilled, by the time it arrives at your place, a few days later, it will be totally inactive and so ineffective.  You will have wasted your money and perhaps falsely concluded that oxytocin is ineffective.

This is how the Sulforaphane is made by Johns Hopkins:-

Preparation of Sulforaphane-Rich Broccoli Sprout Extracts.

Sulforaphane rich broccoli sprout extract (SF-BSE) was prepared by the Cullman Chemoprotection Center at The Johns Hopkins University essentially as described in Egner et al. In brief, specially selected broccoli seeds were surface-disinfected and grown (sprouted) for 3 d in a commercial sprouting facility under controlled light and moisture conditions. A boiling water extract was prepared, filtered, cooled, and treated with the enzyme myrosinase (from daikon sprouts) to convert precursor glucosinolates to isothiocyanates, and

then lyophilized at a food processing facility (Oregon Freeze Dry, Albany, OR). The lyophilized powder (216 μmol SF/g powder) was encapsulated into #1 gelcaps by ALFA Specialty Pharmacy (Columbia, MD); each capsule contained 50 μmol SF (232 mg of SFBSE); placebo capsules were filled with microcrystalline cellulose.

The powders (bulk and capsules) were maintained at approximately

−20 °C and repeatedly checked for microbial contaminants and SF

titer before conveyance to the study site pharmacy (Massachusetts

General Hospital) to be dispensed to patients.

  

Thanks to all the research done on Sulforaphane/broccoli as chemoprotective agent, all the pieces of the puzzle exist.  My first choice would always be the stable analog of Sulforaphane, but it is not yet available and will no doubt be ultra expensive.  So I will work with second best.

The nice people at Johns Hopkins did reply to my questions, so I think I have figured out what I needed to know.

                                           How to make Sulforaphane at home

Regressive Autism and Mitochondria - Part 1

This blog is mainly about classic early-onset autism and the biology underlying it.

There are many other disorders that also result in autistic behaviours, some of which are much better understood than classic autism.  Today’s post is about Mitochondrial Disease which appears to be the precursor to most cases of regressive autism, according to Dr Richard Kelley, at Johns Hopkins and the Kennedy Krieger Institute.

In well-resourced centers for autism, by which I mean large teaching hospitals in the US, cases of autism are often fully investigated.  First they rule out mitochondrial disease and common known single gene causes like Fragile X.  Next comes the chromosome microarray. The microarray (often referred to as CMA) may identify a genetic cause in 15-20% of individuals with an ASD. 

In the rest of the world no such testing takes place, unless you are very lucky.

If the supplement Carnitine makes you feel better, read on, because you quite likely have some mitochondrial dysfunction and have Asperger’s secondary to Mitochondrial Disease.

If you are interested in regressive autism and particularly if you live outside the US, this post could be very relevant.

In short, medical testing can establish whether mitochondrial disease is present.  If it is present, it may be the underlying cause of the regressive autism, or perhaps just an aggravating factor.  If steps are taken quickly, further damage can be limited and the final outcome much improved.

Some of the therapies are the same as for classic autism, like anti-oxidants but some are the opposite.

Certain common drugs should be avoided like types of painkiller (Tylenol/ acetaminophen/paracetamol and aspirin), statins, steroids, valproic acid, risperidone (Risperdal), haloperidol, and some SSRIs; all are inhibitors of complex I / toxic to mitochondria.

There is at least one emerging drug therapy to treat the mitochondria, as opposed to just limit further damage.

The following extensive extracts are all from a paper by Dr Richard Kelley, at the Kennedy Krieger Institute and the neighboring Johns Hopkins Hospital.  I suggest reading the full original paper.  It is the most useful paper related to autism that I have come across, and that is thousands of papers.

Autism secondary to Mitochondrial Disease (AMD)

Evaluation and Treatment of Patients with Autism and Mitochondrial Disease

Most children with autism secondary to mitochondrial disease (“AMD”) experience a single episode of injury, while a few suffer two or more periods of regression during a characteristic window of vulnerability between 12 and 30 months. The subsequent natural history of AMD is typical for regressive autism, with most children showing partial recovery between 3 and 10 years. The principal clinical differences between AMD and non-regressive autism are, variably, a mild myopathy, abnormal fatigue, and, occasionally, minor motor seizures in the years following the first episode of injury. Others with biochemically defined AMD experience a period of only developmental stagnation lasting several months or more between ages 12 and 30 months and show overall better recovery than those who experience a severe autistic regression during this period of neurological fragility. More noteworthy, but uncommonly identified, are sibs of AMD individuals who have all the biochemical features of AMD with no or only minimal developmental or behavioral abnormalities, such as ADHD or obsessive-compulsive disorder.

While permanent developmental losses in AMD can be substantial, especially in the few individuals who suffer more than one episode of regression, recovery can be almost complete in some children when treatment is started early after the first episode of regression, and a partial response to metabolic therapy remains possible indefinitely. Treatment of AMD includes augmentation of residual complex I activity with carnitine, thiamine, nicotinamide, and antothenate, and protection against free radical injury with several antioxidants, including vitamin C, vitamin E, alpha-lipoic acid, and coenzyme Q10 (CoQ10).

Although a deficiency of mitochondrial complex I may be the most common identifiable cause of regressive autism, the relatively mild biochemical abnormalities often are missed by “routine” metabolic testing. In some cases, all test results are in the normal range for the laboratory, but abnormal ratios of metabolites offer clues to the diagnosis.

The identification of patients with AMD has now become routine Kennedy Krieger Institute, in part because of its specialization in both ASD and metabolic diseases and in part because of the availability of onsite biochemical testing.

Natural History of Autism with Mitochondrial Disease. The natural history of AMD and the events surrounding the period of regression are as important as the biochemical abnormalities in establishing the diagnosis. Before regression, all affected children have had normal or even advanced language and cognitive development and no neurological abnormalities apart from mildly delayed gross motor milestones and hypotonia in a few. Regression often can be dated to a specific event, most often a simple childhood illness, such as otitis media, streptococcal pharyngitis, or viral syndrome, or, rarely, an immunization, most often the MMR vaccine or the former DPT. The common feature of all identified precipitants is inflammation. Regression occurs either acutely during the illness or within 14 days of immunization with the MMR attenuated virus vaccine. Regression is otherwise typical for autism and includes acute or subacute loss of language, onset of perseverative behaviors, and loss of eye contact and other social skills. Although neurological regression in many mitochondrial diseases and other metabolic disorders often occurs because of illness-associated fasting, most children with AMD continue to eat normally during the crisis. Moreover, regression during an illness can occur whether or not there is fever. The nature of the regression and its timing suggest that mitochondrial failure is caused by immune-mediated destabilization of mitochondria as part of a TNF-alpha/caspase-mediated apoptosis cascade [5]. Because “steady state” loading of complex I in brain is close to 50% [6,7], if a child had a 50% reduction in complex I activity due to  aplo insufficiency for a complex I null mutation, just a 5 or 10% further reduction in mitochondrial activity could cause neurons to cross the threshold for energy failure and cell death. 

The well-defined role of nutritional factors in modulating the inflammatory response and the shift from animal fats to vegetable-derived fats in western diets are important factors to consider in the cause and treatment of AMD. The increase in the consumption of pro-inflammatory omega-6 fatty acids in infancy and early childhood over the last generation has been particularly striking. The established role of inflammation in causing mitochondrial destabilization [8,9] could explain an increasing incidence of regressive autism in individuals who have otherwise asymptomatic variants of complex I deficiency, which may have specific adaptive function in host defense and cognitive development [10]. In this respect, AMD, which in our experience is the cause of most regressive autism, could be another inflammatory disorder among several that have seen a markedly increased incidence over the last 20 to 30 years: asthma, inflammatory bowel disease, atopic dermatitis, eosinophilic gastroenteritis, and type I diabetes [11]. The recognition of inflammation as an apparently common cause of regression in AMD recommends the use of anti-inflammatory agents, including ibuprofen and leukotriene receptor inhibitors (i.e. montelukast, zafirlukast), to prevent further injury in children with AMD. For example, the recently reported increased risk for post-MMR autistic regression in children given pro-oxidant acetaminophen [12] could also be interpreted as an increased risk for developmental regression in those who were not given ibuprofen. Moreover, the effect of the gradual elimination of aspirin use in children between the 1980s and 1990s following the Reye syndrome epidemic 6 may have contributed to the rise in the incidence of autism, although, epidemiologically, aspirin elimination alone is not likely to be a major factor in the rising incidence of regressive autism.

  

Although most patients with AMD have a discrete episode of acute or subacute language loss and social regression, some will manifest only relative stagnation of development for a period of several months to a year or more. At least 90% of such events––developmental regression or stagnation––occur in a window of vulnerability between 12 and 30 months.

  

The goals for treatment of AMD due to complex I deficiency are:

1)    Augment residual complex I activity

2)    Enhance natural systems for protection of mitochondria from reactive oxygen species

3) Avoid conditions known to impair mitochondrial function or increase energy demands, such as prolonged fasting, inflammation, and the use of drugs that inhibit complex I.

Combining the first and second parts of the treatment plan, the following is a typical prescription for treating AMD:

L-Carnitine 50 mg/kg/d                Alpha Lipoic acid 10 mg/kg/d

Coenzyme Q10 10 mg/kg/d       Pantothenate 10 mg/kg/d

Vitamin C 30 mg/kg/d                  Nicotinamide 7.5 mg/kg/d (optional)

Vitamin E 25 IU/kg/d                    Thiamine 15 mg/kg/d (optional)

Immediate behavioral improvement with carnitine treatment in a child with regressive autism makes complex I deficiency the most likely cause

Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.

When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period. Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours. 

the MMR vaccine has been temporally associated, if rarely, with regression in AMD and other mitochondrial diseases when given in the second year. Doubtless some of these regressions are coincidental, since the usual age for giving the MMR falls within the typical window of vulnerability for AMD regression. In some children, however, MMR-suspected regression has coincided with the peak inflammatory response on days 8 to 10 post-immunization, as measured by IL-10 levels [28]. Unfortunately, the falling rates of immunization with MMR in the United States and other countries all but guarantees that major outbreaks of measles, mumps, and rubella will occur in the near future

Nutritional Factors Diet is another variable to consider in the treatment of AMD. Vegetable oils that are “pro-inflammatory” due to low levels of omega-3 (n-3) fatty acids and increased amounts of linoleic acid and other omega-6 (n-6) fatty acids today predominate in infant formulas and most prepared foods, largely because 13 of nutritional recommendations to avoid animal fats containing saturated fatty acids and cholesterol. The serious consequences of this trend are now being felt. A study in 2000 [29] showed that two- to four-month old breast-fed infants had more than twice the level of docosahexaenoic acid (C22:6n-3) and higher levels of most other n-3 fatty acids compared to formula-fed infants, although immunological consequences of the difference could not be demonstrated using limited immunological assays in that particular study. While the average child may suffer no obvious ill effects from diets deficient in n-3 fatty acids, the possible proinflammatory effect of these diets could be a contributing factor to infection-induced regressive autism in a child who has a metastable mitochondrial disorder. Moreover, in view of a recent study that associated decreased synthesis of cholesterol with rare cases of non-regressive autism [30], the early termination of breast-feeding and the major shift in infant diets toward low-cholesterol vegetable fats could be contributing factors to the apparent rise in the incidence of both regressive and non-regressive autism. Indeed, studies over the last two decades have shown that absence or early termination of breast-feeding is associated with higher rates of autism [31]. The simplest way to assure a adequate amount of C22:6n-3 and related fatty acids for children on typical vegetable-oil enriched diets is to provide an oil supplement, such as flaxseed oil, which is enriched in the precursors for C20 and C22 n-3 fatty acids, or salmon oils, which contain substantial amounts of DHA and EPA and a relatively low mercury content compared to many other fish species. C. Medications Certain behavior medications used in the treatment of ASD are inhibitors of complex I and, therefore, warrant consideration in treating children with AMD. Although these medications appear to have little effect on overall energy metabolism in individuals with normal mitochondria, clinically significant compromise of mitochondrial function can occur when complex I is impaired and relatively high doses of the more inhibitory drugs are prescribed. The complex I-inhibiting drugs most likely to be used in the treatment of ASD include both typical and atypical neuroleptics, such as risperidone (Risperdal), haloperidol, and some SSRIs. Although these medications are used most often in older children who are beyond the vulnerable period for autistic regression, this theoretical risk should be considered when prescribing older generation neuroleptics, such as haloperidol and related drugs, with a higher risk for development of tardive dyskinesias.

These older neuroleptics have been shown to inhibit complex I activity in direct proportion to their propensity to cause tardive dyskinesia [32]. However, there is no evidence that the newer “atypical” neuroleptics, such as risperidone and quetiapine, which have a low risk for extrapyramidal damage, are contraindicated in children with AMD and other mitochondrial diseases. Indeed one of the commonly used atypical neuroleptics, risperidone, has been shown to possibly against mitochondrial injury via modulation of damaging stress induced calcium influxes into mitochondria [33].

Novel Mitochondrial Drugs

Edison Pharmaceuticals is developing treatments for mitochondrial disease.

EPI - 743

  

EPI-743 is a drug candidate in clinical development primarily focused on inherited mitochondrial diseases. EPI-743 is administered orally, passes into the brain, and works by regulating key enzymes involved in the synthesis and regulation of energy metabolism.
Through expanded access protocols and prospective clinical trials, EPI-743 has been dosed for more than a cumulative 130,000 patient dosing days (as of November, 2013), and has recorded a favorable human safety profile. Subjects with over 15 discrete diseases have been treated. 

EPI-743 reverses the progression of the pediatric mitochondrial disease—Genetically defined Leigh Syndrome

Genetic Dysfunctions

The prevalence of mitochondrial disorders (excluding autism) is estimated to be about 1:8500

Mitochondrial Disorders Overview

and yet it is estimated that 1 in 200 people have a defective gene linked to a mitochondrial disorder. 

Pathogenic Mitochondrial DNAMutations Are Common in the General Population

This implies a multiple hit mechanism, like we saw with cancer in an earlier post.  It also shows the potential to be misled by genetic information.  Just because the defect is there does not mean it will actually cause anything to happen, further rare events may also be needed to trigger it.

Alternatively, maybe there are far more people with a mitochondrial disease than the above studies suggest.  They are not including people with regressive autism, for one.  Something like 1 in 200 people have regressive autism.

  

What happened to Dr Richard Kelley?

If you have read the full paper by Dr Kelley you are probably wondering what else he has to say about autism.  He is an extremely rare mainstream clinician who actually does know about the subject.

You might also be wondering how come such a doctor can write about vaccination triggering mitochondrial disease and then autism, albeit in rare cases.

Perhaps this is why he does not write further about autism?

Dr.Kelley's research has focused on the elucidation of the biochemical basis of genetic disorders. Through the application of various techniques of biochemical analysis but especially mass spectrometry, Dr. Kelley has discovered the biochemical cause, and thereby the genetic etiology, of more than a dozen different diseases.

People do write about autism and mitochondrial disease, but some of these researchers are from the fringe and are not taken very seriously by the mainstream.

Intermittent Explosive Disorder (IED) + Autism

An altogether different kind of IED, although you may not always feel so.

Many people think that childhood psychiatric disorders, including autism, are grossly over-diagnosed in the US.

This did spring to mind when I came across a reference to “intermittent explosive disorder” and autism.

Before we get into that, I received an interesting graphical presentation of ADHD in the US, from a company called Healthline; they want me to give a link on my post on Clonidine.  It shows many things including how ADHD diagnosis varies wildly by State, just as the CDC’s autism data does.  The difference is remarkable. I don’t think anybody really believes that ADHD is 3 times more prevalent in Kentucky than in Nevada.  It just shows how inconsistent the diagnosis is; perhaps you could correlate the diagnosis with the medical school attended by the doctor/psychiatrist?

Back to Intermittent Explosive Disorder

Intermittent explosive disorder (IED) is a behavioral disorder characterized by explosive outbursts of anger, often to the point of rage, that are disproportionate to the situation at hand.

  

This is pretty tame stuff to many carers of anyone with autism.  So I thought it odd that anyone bothered to diagnose autism + IED.

The question is usually where the IED is directed, to the carer or to self (Self Injurious Behavior).

So IED is a normal part of autism, but it can be treated, without recourse to the drugs psychiatrists use.  They often cause further problems.

I was curious to find out what the research says about IED in other people.  Rather surprisingly, or maybe not, the mechanism turns out to be the same.

IED in Autism

Regular readers will recall the posts all about inflammatory agents (cytokine IL-6 and histamine) that turned out to trigger the summertime raging in Monty, aged 11 with ASD.

Using Verapamil to stabilize the mast cells and so lower the level of histamine and IL-6, I made the raging and aggression go away.  It really does work.

IED in Everyone Else

Elevated plasma inflammatory markers in individuals with intermittent explosive disorder and correlation with aggression in humans.

press release

"The researchers measured the inflammatory markers CRP (C Reactive Protein) and IL-6 levels in 197 physically healthy volunteer subjects. Sixty-nine of those subjects had been diagnosed with IED, 61 had been diagnosed with psychiatric disorders not involving aggression, and 67 had no psychiatric disorder.

Both CRP and IL-6 levels were higher, on average, in subjects with IED, compared to either psychiatric or normal controls. Average CRP levels, for example, were twice as high for those with IED as for normal healthy volunteers. Both markers were particularly elevated in subjects who had the most extensive histories of aggressive behaviors. Each marker independently correlated with aggression, the authors note, suggesting that "both have unique relations with aggression."

Overall, the findings reported in this new paper suggest that "medications that reduce inflammation may also drive down aggression," Coccaro said. Anti-inflammatories such as Celebrex, or even aspirin, might make a difference for those with IED. Since available treatments bring less than 50 percent of patients into remission, the authors wrote, "additional strategies for the examination and intervention of human impulsive aggression are needed."

Pass the NAC, please

Not surprisingly people with IED also tend to suffer from oxidative stress.

Elevated Plasma Oxidative Stress Markers in Individuals with Intermittent Explosive Disorder and Correlation with Aggression in Humans

Background

Animal and clinical studies suggest a link between inflammation and oxidative stress. Because oxidative stress is an inherent part of inflammation, and inflammation is associated with behavioral aggression in lower mammals and humans, we hypothesized that markers of oxidative stress would be related to aggression in human subjects. In this case-control study, markers of oxidative stress and aggression were assessed in human subjects with histories of recurrent, problematic, impulsive aggressive behavior and in nonaggressive comparator subjects.

Conclusions

These data suggest a positive relationship between plasma markers of oxidative stress and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of aggression in human subjects.

I had one reader tell me that the most noticeable effect of the antioxidant NAC on her son with autism, was that he stopped biting her.  One less IED to defuse in her house.

ABA is also a potent tool to understand the underlying cause of aggression and SIB; but if you suffer from neuro-inflammation and oxidative stress, even ABA can do with a little extra help.

Yale, Autism and Morphology

  

In a recent post I introduced a new term – morphology.  Some scientific jargon serves to make things more confusing for the lay reader, but this really is a useful term to understand autism.

Morphology, in biology, the study of the size, shape, and structure of animals, plants, and microorganisms and of the relationships of the parts comprising them.

Today we are talking about morphology as it relates to the growth of the human body in autism.

In earlier posts relating to hormones and growth factors (endocrinology) I made my own observations about Monty, aged 11 with ASD.  I commented how he fell from the 80% percentile in height, aged 2, to the 20^th percentile, where he is now.  I also noted how he went from very muscular to your average “floppy” toddler.

I did discuss this with a pediatric endocrinologist and asked what is the point of collecting this height and weight data for children, if nothing is done with it.  I did tell her all about the emerging use of the growth factor IGF-1 in treating autism and also the hypothesis that people with autism have low thyroid hormone T3 in the brain.

I concluded that endocrinologists do not know anything about autism, but I did learn all about bone age. 

Endocrinologists often use X rays of the hand to look for advanced or delayed bone age.  They look at the gaps in between the small bones to assess the degree of maturation.  The bigger the gap, the less mature the bones.  They have a big book of X-rays and they just flip through the pages until they find one like your X ray.  So if you are 11 years old, with bone structure of a 9 year old, then you would have delayed bone age.  In practical terms, this means you are likely to keep growing for longer than the average child.

Autism Research

As we have seen already, much data in autism is of dubious quality.  Studies are contradictory.  Much of this is due to mixing apples with kiwis and even pineapples. You cannot usefully compare data on severely autistic people with those ever so mildly affected, but still “autistic” by DSM. Even separating early onset and regressive autism is rare in studies.  There is no agreement as to what regressive really means and some scientists even think regression is just a development plateau – I guess they never see actual patients.

So I was pleased to come across some interesting research about autism morphology that seems credible.  Of all places, it was in a student publication from Yale.  On Facebook, Monty’s older brother keeps getting confused with his namesake, who is one of the reporters on the Yale student newspaper.    Not only does Yale have a daily student newspaper, but it also has its own Yale Scientific Magazine.

They must have a lot of free time over at Yale.

This was my first experience of student journalism at Yale.  I was impressed.

Autism may be predicted by overgrowth

Sizing Up Autism: The CorrelationBetween Autism and Abnormal Growth

  

One identified phenotype associated with autism is abnormally large Total Cerebral Volume (TCV) and, correspondingly, Head Circumference (HC) – collectively called macrocephaly. Researchers at Yale University’s Child Study Center have undertaken studies in the connectivity of growth and neural development to assess risk and predict developmental phenotype of young boys through growth measurement. A group of 184 boys aged birth to 24 months, composed of 55 typically developing controls, 64 with ASD, 34 with Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), 13 with global developmental delays, and 18 with other developmental problems, was analyzed for head circumference, height, weight, and social, verbal and cognitive functioning. Boys with autism were significantly taller by 4.8 months, had a larger HC by 9.5 months, weighed more by 11.4 months, were in the top ten percent in size in infancy (correlated with lower adaptive functioning and social deficits), and showed accelerated HC growth in the first year of life.  


Here is actual study:-

Early Generalized Overgrowth in Boys With Autism

Main Outcome Measures: Age-related changes in HC (head circumference),

height, and weight between birth and age 24 months; measures of social, verbal, and cognitive functioning at age 2 years.

Results: Compared with typically developing controls, boys with autism were significantly longer by age 4.8 months, had a larger HC by age 9.5 months, and weighed more by age 11.4 months (P=.05 for all). None of the other clinical groups showed a similar overgrowth pattern. Boys with autism who were in the top 10% of overall physical size in infancy exhibited greater severity of social deficits (P=.009) and lower adaptive functioning (P=.03).

Conclusions: Boys with autism experienced accelerated HC growth in the first year of life. However, this phenomenon reflected a generalized process affecting other morphologic features, including height and weight. The

study highlights the importance of studying factors that influence not only neuronal development but also skeletal growth in autism.

  

The Yale researcher is Polish, as was the lady who wrote about oxidative stress in the brain lowering D2 and hence thyroid hormone T3 in the brain.

Conclusion

This does take us back to the earlier posts on human growth factors.  It does seem that at least in one sub-type of autism there is “excess” growth in the first two years that is visible in terms of morphology.  This growth spurt then halts.

We already have data showing that in autism the brain itself also “over-grows” up to the age of about three.  We can now generalize that in this sub-type everything is likely affected by this over-growth.

Why does the growth spurt halt? It is not for lack of the growth factor IGF-1, many people with autism actually have elevated levels of this growth factor.  It is simple and inexpensive to check; I did it.

The problem may relate to something called Akt, also known as protein kinase B (PKB).

IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation.

Very recent research has highlighted abnormalities in the IGF-1 – Akt pathway and also in similar pathways related to the brain’s own growth factor, BDNF.  (Note that mTOR is also implicated in autism)

Dysregulation of the IGF-I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders

 Abnormalities in BDNF/TrkB/PI3Ksignaling pathways in autism

So while IGF-1 may be an effective therapy for some people with autism (it is already used experimentally), most likely the real problem is slightly different and a better intervention might relate to AKT/PKB.

We will follow up on these and other protein kinase shortly.